N&#39;-propargyl-n**2-cyclopropyl-ethylenediamines and the salts thereof



United States Patent 1967, Ser. No. 671,621

Int. Cl. C07c 87/28, 137/36 US. Cl. 260-563 10 Claims ABSTRACT OF THEDISCLOSURE N'-cyclopropy1 ethylenediamine derivatives and thepharmaceutically acceptable nontoxic salts thereof are useful asantidepressants and monoamine oxidase inhibitors in mammals.

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a divisionalapplication of application Ser. No. 454,972, filed May 11, 1965, and nowUS. Pat. No. 3,365,458, which is a continuation-in-part of now abandonedapplication Ser. No. 377,387, filed June 23, 1964.

BACKGROUND OF THE INVENTION Field of the invention This inventionrelates to novel compounds. More particularly, this invention relates tonovel compounds which possess valuable therapeutic utility asantidepressants and monoamine oxidase inhibitors, and to intermediatesuseful in the preparation thereof. In another aspect, this inventionrelates to a novel method of treating depression.

Description of the prior art There exists a need to provide additionalagents useful as antidepressants and monoamine oxidase inhibitors. Thus,it is an object of this invention to provide a new class of compoundshaving antidepressant activity. Another object of the present inventionis to provide novel compounds which inhibit the enzyme monoamineoxidase. It is a still further object of the present invention toprovide a novel method of treating depression.

SUMMARY OF THE INVENTION The above and other objects which may appear asthe specification proceeds are achieved by this invention whichcomprises the provision of compounds selected from the group consistingof compounds having the formula and the pharmaceutically acceptablenontoxic salts thereof. In Formula I, R is a member selected from thegroup consisting of (lower) alkynyl, thienyl, furyl, pyridyl, pyrrolyl,naphthyl and Ph-, wherein Ph is a radical of the formula wherein R and Rare each a member selected from the group consisting of hydrogen,chloro, bromo, iodo, fluoro, trifluoromethyl, (lower)alkyl,(lower)alkoxy, (lower)- alkylthio, di-(lower) alkylsulfamyl, phenyl,phenoxy, benzyl, and when taken together, methylenedioxy; R and R may bethe same or diiferent in each occurrence;

n is a whole integer from 0 to 1 inclusive;

R is a member selected from the group consisting of hydrogen,(lower)alkyl, (lower)alkenyl, (lower)alkynyl, and cycloalky radicashaving from 3 to 7 carbon atoms, inclusive, e.g. cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl;

R is a member selected from the group consisting of hydrogen,(lower)alkyl, (lower)alkenyl, (lower)alkynyl, phenylalkyl, wherein thealkyl moiety contains from 1 to 4 carbon atoms, inclusive, andphenylalkenyl, wherein the alkenyl moiety contains from 2 to 4 carbonatoms, inclusive;

R is a member selected from the group consisting of hydrogen,(lower)alkyl, (lower)alkenyl, (lower)alkynyl, Ph-, Ph-alk-, andPh-alken-, in which Ph is as represented above, alk represents adivalent alkylene radical containing from 1 to 4 carbon atoms,inclusive, and

Y is a member selected from the group consisting of (lower)alkylene,(lower)alkenylene, (lower)alkynylene, oxy(lowcr)alkylene andmercapto(lower) alkylene.

DETAILED DESCRIPTION The pharmaceutically acceptable nontoxic saltsinclude the organic and inorganic monoand diacid addition salts, e.g.,those prepared from acids such as hydrochloric, sulfuric, sulfamic,tartaric, fumaric, hydrobromic, hydriodic, glycolic, citric, maleic,phosphoric, succinic, acetic, nitric, and the like.

The term (lower)alkyl as used herein means both straight and branchedchain alkyl radicals containing from 1 to 8 carbon atoms, e.g. methyl,ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl,2-ethylhexy1, etc.

The term (lower)alkenyl as used herein means both straight and branchedchain alkenyl radicals containing.

from 2 to 8 carbon atoms, e.g. ethenyl, allyl, l-propenyl, l-butenyl,S-butenyl, Z-methyl-l-propenyl, 3-pentyl, 1- hexenyl, 7-octenyl, etc.

The term(lower)alkenyl as used herein means both straight and branchedchain alkynyl radicals containing from 2 to 8 carbon atoms, e.g.ethinyl, propargyl, 1- butinyl, Z-butinyl, 1-1-dimethylpropargyl,l-pentinyl, 1- heptinyl, etc.

The term (lower)alkylene as used herein means both straight and branchedchain alkylene radicals containing from 1' to 8 carbon atoms, e.g.methylene, ethylene, octylene, propylene, butylene, isobutylene,t-butylene, amylene, hexylene, 2-ethyl-hexylene, etc.

The term (lower)alkenylene as used herein means both straight andbranched chain alkenylene radicals containing from 1 to 8 carbon atoms,e.g. ethenylene, 1- propenylene, 3-butenylene, Z-methyl-l-l-butenylene,etc.

The term (lower)alkynylene as used herein means both straight andbranched chain alkynylene radicals containing from 1 to 8 carbon atoms,e.g. ethinylene, propargylene, l-propinylene, 3-butinylene,1,1-dimethyl-3-butinylene, hexinylene, octinylene, etc.

Similarly, where the term (lower) is used as part of the description ofanother group, e.g., (lower)alkoxy, it refers to the alkyl portion ofsuch group which is '3 6 therefore as described in connection with(lower)alkyl.

Preferred compounds of the present invention are those having thefollowing formulae l HCEC(Y)DNCH2OH2-1\II I wherein n, R R R R R and Yare as represented above.

Still more preferred compounds of the present invention are those havingthe following formulae (XVI) R Preferred individual compounds of thisinvention are those having the formulae (XXI) (XXIII) The compounds ofthis invention are valuable pharmaceutical agents. They produce markedincrease in central nervous system activity which makes the compoundsuseful as antidepressant agents. In addition, the compounds inhibit theenzyme monoamine oxidase which makes the compounds useful as monoamineoxidase inhibitors.

It is generally accepted that elevation of certain brain amines resultsin psychic effects clinically. These efiFects take the form of moodelevation or antidepressant action.

Brain norepinephrine and serotonin are brain amines chiefly metabolizedby the enzyme monoamine oxidase. Inhibitors of this enzyme produce acharacteristic elevation of these brain amines; and the ability of acompound to increase the level of brain norepinephrine and serotonin iswell correlated with central monoamine oxidase inhibition.

The effect of the compounds of this invention on brain norepinephrineand serotonin was determined in mice by the method of Shore et al. (J.Pharmacol. 112, 295 300, 1958), as modified by Mead et al. (Bioch.Pharmacol. 6, 52-53, 1961), for the simultaneous extraction of bothnorepinephrine and serotonin from the same homogenate. The methodinvolves extraction of norepinephrine and serotonin into butanol, returnof the amines to an aqueous phase and conversion to a fluorescentderivative. Norepinephrine was determined by oxidation at pH 5, totrihydroxyindole, and serotonin by its native fluorescence in 3 Nhydrochloric acid. The brains of eight mice Were pooled for eachdetermination,

and the compound was administered orally. The level of brain amines wasdetermined at diiferent intervals after administration, and a controlgroup was run in each experiment.

The results for a preferred compound of the present invention,N-benzyl-N-methyl-N-cyclopropylethylenediamine, are summarized in thefollowing table and show that the compound is a potent elevator of brainamines, and is, therefore, a powerful antidepressant agent.

Percent; increase in concentration over Time control after g,Norepinhours ephrine Serotonin Dose, mg./kg.:

The results for another preferred compound of the present invention,N-methyl-N-propargyl-N-cyclopropyl N-benzylethylenediaminedihydrochloride, are summarized in the following table and show that thecompound is a potent elevator of brain amines, and is, therefore, apowerful antidepressant agent.

Brain amine level, percent lncrease over The compounds of this inventionare also capable of preventing the sedative effects of reserpine inmice. Oral administration of as little as 10 mg./kg. of a preferredcompound of the present invention, N-benzyl-N-methyl- Ncyclopropylethylenediamine, in mice three hours before intravenousadministration of mg./kg. of reserpine completely prevented symptomsusually associated with reserpine administration, i.e. increased motoractivity, profuse salivation, and ptosis. Thus, the preferred compoundof the present invention is a powerful monoamine oxidase inhibitor, andexhibits marked antidepressant activity. N- benzyl N methyl Ncyclopropylethylenediamine eX- hibited an oral LD in mice of 849 mg. kg.

Another preferred compound, N-methy LN-propargyl- N benzyl Ncyclopropylethylenediamine dihydrochloride, had a minimum effective doseof mg./kg. and an oral LD in mice of 420 mg./ kg.

The compounds of the present invention are prepared by the acylation ofa primary or a secondary cyclopropylamine of the formula Rs N t.

(XXIV) wherein R and R are as represented above with anochaloacetylhalide or an a-tosylacetylhalide of the formula (XXV) (u)X-OH2-C-Z wherein X is chloro, bromo, iodo, fluoro, or tosyl, and Z ischloro, bromo, iodo, or fluoro, in the presence of an acid acceptor suchas potassium carbonate, pyridine, triethylamine or sodium hydroxide inan aqueous acetone or benzene solution to yield an N-cyclopropyla-haloor tosylacetamide of the formula (XXVI) R wherein X, R and R areas represented above. This procedure is generally described in US. Pat.No. 2,569,288. Representative of the primary cyclopropylamines which maybe used in this process are,

cyelopropylamine,

,B-methylcyclopropylamine, ,B-ethylcyclopropylamine,fi-allylcycloprovpylamine, fl-propargylcyolopropylamine,3-phenylcyclopropylamine, fl-para-trifluoromethylphenylcyclopropylamine,B-para-chlorophenylcyclopropylamine,fi-para-ethoxyiphenylcyclopropylamine,[3-3,4-methylenedioxyphenylcyclopropylamine, and fl-para-methylthiophenylcyclopropylamine.

Representative of the secondary cyclopropylamines which may be employedare,

N-cyclopropyl-N-methylamine, N-cyclopropyl-N-isopropylamine,N-cyclopropyl-N-allylamine, N-cyclopropyl-N-propargylamine,N-cyclopropyl-N-benzylamine, N-cyclopropyl-N-phenylisopropylamine,N-cyclopropyl-N-cinnamylamine, N-B-phenylcyclopropyl-N-methylamine,N-fi-(m-trifluoromethyl)phenylcyclopropyl-N-methylamine,N-fl-(p-fluoro)phenylcyclopropyl-N-allylamine,N-B-(m,p-methylenedioXy)phenylcyclopropyl-N- propargylamine, andN-fl-(o-methylmercapto)phenylcyclopropyl-N-benzylamine.

Some of the a-haloor tosylacetamide halides which may be used in thisprocess are,

ot-chloroacetyl chloride, a-brom-oacetyl chloride, u-iodoacetyl bromideand u-para-tosylacetyl chloride.

Some of the N'-cyc lopropyl a-haloor tosylacetamides thus formed are,

N-cyclopropyl a-chloroacetamide, N-Z-methylcyclopropyl u-bromoacetamide,N-Z-phenylcyclopropyl a-iodoacetamide, N-2-allylcyclopropyla-chloroacetamide, N-Z-propargylcyclopropyl tat-tosylacetamide,N-2-(m-trifluoromethyl)phenylcyclopropyl a-ChlOIO- acetamide,N-2-(p-fluoro)phenylcyclopropyl a-bromoacetamide,N-2-(o-bromo)phenylcyclopropyl a-chloroacetarnide,N-2-(p-ethoxy)pheny1cyclopropyl a-bromoacetamide,N-2-(m,p-methylenedioxy)phenylcyclopropyl a-ChlOI'O- acetamide,N-Z-(o-methylmercapto)phenylcyclopropyl oc-Ch-lOIO- acetamide,N-cyclopropyl-N-methyl a-bromoacetamide, N-cyclopropyl-N-isopropylu-bromoacetamide, N-cyclopropyl-N-benzyl a-bromoacetamide,N-Z-methylcyclopropyl-N-allyl a-bromoacetamide,N-2-phenylcyclopropyl-N-propargyl a-iodoacetamide,N-2-(m-trifluoromethyl)phenylcyclopropyl-Napropargyl a-iodoacetamide,N-2-allylcyclopropyl-N-methyl a-bromoacetamide,

N-2-(p-fluoro)phenylcyclopropyl-N-benzyl oc-bIOl'IlO- acetamide,

N-cyclopropyl-N-propargyl u-bromoacetamide,

N-2-phenylcyclopropyl-N-methyl a-bromoacetamide,

N-2-(o-chloro)phenylcyclopropyl-N-methyl a-bromoacetamide andN-2-(o-methyl)phenylcyclopropyl-N-propargyl a-bromoacetamide.

The N'-cyclopropyl a-haloor tosylacetamides are converted toN-cyelopropylglycinarnides of the formula (XXVII) s R-(Y) .1 I-om1wherein R, R R R 11 and Y are as represented above, by reacting theacetamide with a primary or secondary amine in the presence of an acidacceptor such as triethylamine, potassium carbonate, aminopyrine,N-ethylaniline and an inert solvent such as benzene, toluene, Xylene,dimethylformamide, dioxane, at elevated temperatures, e.g., refluxtemperature. Isolation of the desired N'-cyclopropylglycinamide is thenbrought about by fractional distillation or crystallization. This stepis generally described in US. Pat. No. 2,937,180.

Some of the primary amines which may be used in this step of the processare,

aniline, m-trifluoromethylaniline, o-bromoaniline, o-methylaniline,p-proparglyoxyaniline, p-ethoxyaniline, m-methoxyaniline,o-methylmercaptoaniline, benzylamine, u-methylbenzylamine,u-isopropylbenzylamine, o-chlorobenzylamine, p-fiuorobenzylamine,m-trifluoromethylbenzylamine, o-methylmercaptobenzylamine,p-ethoxybenzylamine, p-proparglyoxybenzylamine,m,p-methylenedioxybenzylamine, p-phenoxybenzylamine,p-phenylbenzylamine, p-dialkylsulfamylbenzylamine, a-napthylamine,S-naphthylamine, u-naphthylmethylamine, fl-napthylmethylamine,phenylisopropylamine, p-fluorophenylisopropylamine,m-trifluoromethylphenylisopropylamine, p-ethoxyphenylisopropylamine,o-methylmercaptophenylisopropylamine, o-methylphenylisopropylamine,a-thienylmethylamine, B-thienylmethylamine, Z-furfurylmethylamine,2-pyridylmethylamine, 3-pyridylmethylamine, 4-pyridymethylamine,2-pyridylethylamine, 3-pyridylethylamine, 4-pyridylethy1amine,l-pyrrolylmethylamine, propargylamine, ethinylamine, and butinyl.

Some of the secondary amines which may be used in this step of theprocess are,

8 N-phenyl-N-methylamine, N-phenyl-N-propargylamine,N-phenyl-N-allylamine, N-phenyl-N-cyclopropylamine,-N-phenyl-N-cyclobutylamine, N-phenyl-N-cyclopentylamine,N-benzyl-N-methylamine, N-benZyl-N-allylamine, N-benzyl-N-propargylamine, N-benzyl-N-cyclopropylamine, N-benzyl-N-cyclobutylamine,N-benzyl-N-cyclopentylamine, N -benzyl-N-cycloheptylamine,-N-benzyl-N-cyclooctylamine, N-p-ethoxyphenyLN-methylamine,N-p-chlorophenyl-N-methylamine, N-o-bromophenyl-N-methylamine,N-m-trifiuoromethylphenyl-N-methylamine,N-3,4-methylenedioxyphenyl-N-methylamine,N-o-methy1mercaptophenyl-N-methylamine,N-p-dialkylsulfamylphenyl-N-methylamine, N-o-methylphenyl-N-methylamine,N-o-methylbenzylN-methylamine, N-o-bromobenzyl-N-methylamine,N-p-fluorobenzyl-N-methylamine, N-m-trifiuromethylbenzyl-N-methylamine,-N-p-ethoxybenzyl-N-methylamine, N-p-proparglyoxybenzyl-N-methylamine,N-p-phenoxybenZyl-N-methylamine, N-p-phenylbenzyl-N-methylamine, N-3,4-methylenedioxybenzyl-N-methylamine,N-o-methylmercaptobenzyl-N-methylamine,N-p-dialkylsulfamylbenzyl-N-methylamine,N-o-methylbenzyl-N-propargylamine, N-o-bromobenZylN-propargylamine,N-p-fiuorobenzyl-N-propargylamine,N-m-trifluoromethylbenzyl-N-propargylamine,N-p-ethoxybenzyl-N-propargylamine,N-p-propargyloxybenzyl-N-propargylamine,N-p-phenoxybenzyl-N-propargylamine, N-p-phenylbenzyl-N-propargylamine,N-3,4-methylenedioxybenZyl-N-propargylamine,N-o-methylmercaptobenzyl-N-propargylamine,N-p-dialkylsulfamylbenzylN-prop argylamine, N-methyl-N-propargylamine,N-ethyl-N-propargylamine, N-isopropyl-N-propargylamine,N-allyl-N-propargylamine, N-butenyl-N-propargylamine,N-propargyl-N-propargylamine, N-cyclopropyl-N-propargylamine,N-methyl-N-ethinylamine, and N-methyl-N-butinylamine.

Conversion of the N'-cyclopropylglycinamides to the ethylenediamines ofthis invention having the formula (XXVIII) RN-phenyl-N'-cyclopropylethylenediamine,N-phenyl-N-methyl-N-cyclopropylethylenediamine,N-phenyl-N-propargyl-N'-cyclopropylethlenediamine,

N-phenyl-N-benzyl-N-cyclopropylethylenediarnine, N-(m-tritluoromethylphenyl)-N-cyc1opropyl-N-cyclopropyl-N'-methy1ethylenediamine,N-(p-chlorophenyl)-N-propargyl-N-(2-phenylcyclopropyl)-N'-propargylethylenediamine,N-(p-ethoxyphenyl)-N-cinnamyl-N-(2methylcyclopropyl)-N'-5'-phenethylethylenediamine, N-benzyl-N'-cyclopropylethylenediamine,N-benzyl-N-methyl-N'-cyclopropylethylenediamine,N-benzyl-N-a]lyl-N'-cyclopropylethylenediamine,N-benzyl-N-propargyl-N-cyc1opropy1ethylenediamine,N-benzyl-N-cyc1opropyl-N'-cyclopropylethylenediamine,N-benzyl-N-cyclopropylmethyl-N'-cyclopropylethylenediamine,N-o-chlorobenzyl-N-methyl-N-cyclopropylethylenediamine,N-m-trifluoromethyl-N-methy1-N'-cyclopropyl-N'-propargylethylenediamine,N-p-ethoxybenzyl-N-methyl-N-cyc1opropy1-N-methylethylenediamine,N-o-methylmercaptobenzy1-N-methy1-N'-cyclopropyl-N'-propargylethylenediamine,N-p-phenoxybenzyl-N-methyl-N-cyclopropyl-N-}8-phen ethylethylenediamine,N-p-phenylbenzyl-N-allyl-N'-2-methylcyclopropy1-N'-cinnamylethylenediamine,N-benzyl-N-methyl-N'-2-phenylcyclopropylethylenediamine,N-benzyl-N-methyl-N'-2-(m-trifluorornethylphenyl)cyclopropylethylenediamine, N-benzyl-Nmethyl-N'-2- (o-chlorophenyl)cyclopropylethylenediamine, N-benzyl-N-methyl-N'-2-phenylcyclopropyl-N'-methylethylenediamine,N-benzy1-N-rnethy1-N'-2-phenylcyclopropyl-N'-propargylethylenediamine,N-benzyl-N-methyl-N-cyclopropyl-N-cinnamylethylenediamine,N-benzyl-N-methyl-N', '-biscyclopropylethylenediamine,N-(4-diethylsulfamylbenzyl)-N-methyl-N-cyclopropylethylenediamine,N-cinnamyl-N-methyl-N'-cyclopropylethylenediamine,N-a-methylphenethyl-N-methyl-N-cyclopropylethylenediamine,N-a-methyl-B-phenoxyethyl-N-methyl-N-cyc1opropylethylenediamine,N-methyl-N-propargyl-N benzyl-N'-cyclopropylethylenediamine,N-methyl-N-propargyl-N'-benzyl-N-;3-methylcyclopropylethylenediamine,N-methyl-N-propargyl-N'-benzyl-N'-,B-allylcyclopropylethylenediarnine,N-methyl-N-propargyl-N-benzyl-N'-fi-phenylcyclopropylethylenediamine,N-methyl N propargyl-N'-phenyl-N-cyclopropylethylenediamine,N-ethyl-N-propargyl-N'-benzyl-N-cyclopropylethylenediamine,N-isopropyl-N-propargyLN benzyl-N'-cyc1opropylethylenediamine,N-allyl-N-propargyl-N'-benzyl-N'-cyc1opropylethylenediamine,N-butenyl-N-propargyl-N-benzyl-N-cyclopropylethylenediamine,N-propargyl-N-propargyl-N benzyl-N cyclopropylethylenediamine,N-cyclopropyl-N-propargy1-N'-benzyl-N-cyclopropylethylenediamine,N-methyl-N-butinyl-N'-benzyl-N'-cyclopropylethylenediamine,N-methyl-N-cthinyl-N'-benzyl-N'-cyclopropylethylenediamine,N-propargyl-N-cyclopropylethylenediamine, N-propargyl-N-benzylN'-cyclopropylethylenediamine,

and

N-methyl-N-propargyl N-cyclopropylethylenediamine.

The tertiary cyclopropylethylenediamines of Formula XXVIII but wherein Ris other than hydrogen, may also be produced by reacting a secondarydiamine such as N-benzyl N methyl N'cyclopropylethylenediamine with areactive alkyl, alkenyl, alkynyl, aralkyl, aralkenyl or aralkynyl halidein the presence of an acid acceptor such as triethylamine, potassiumcarbonate and an inert solvent such as benzene or toluene; and thenmethylating the secondary amine with formaldehyde and formic acid.

The tertiary ethylenediamines of this invention may also be produced byreacting a secondary diamine such as N-methyl N-benzyl-N'cyclopropylethylenediamine with a Grignard reagent such asmethylmagnesium bromide and allowing the resulting magnesium amide saltto interact with a reactive halide such as propargyl bromide. Thismethod may be carried out according to the following reaction scheme:

An alternate process of forming the diamines of Formula I consists offorming an u-haloacetamide of the formula (XXIX) H R-(Y)nNCOH2X whereinR, Y, n, R and X are as represented above according to the generalprocedure described above for preparing the N'-cyclopropyla-haloacetamides of Formula XXVI and then allowing the a-halo group toreact with a primary or secondary cyclopropylamine of For mula XXIV'toyield an N-cyclopropylglycinamide of the formula (XXX) R O Ramaacaqtwherein R, Y, n, R R and R are as represented above.

11 1243-1265 (1962), US. Pats. Nos. 3,079,403, 3,081,336 and 3,083,226;British Pat. No. 913,898; and Canadian Pat. No. 685,776, etc.; and thepreparation of various propargylamines is described in J. Med. Chem. 7,390 (1964).

The compounds of this invention may be administered as the free bases orin the form of their nontoxic addition salts. They may be compounded andformulated into pharmaceutical preparations in unit dosage form for oralor parenteral administration with organic or inorganic solid materialsor liquids which are pharmaceutically acceptable carriers. Thecompositions may take the form of tablets, powder granules, capsules,suspensions, solutions and the like. Such compositions are consideredwithin the scope of this invention.

The compositons of this invention when administered orally orparenterally, in an effective amount, are effective in the treatment ofdepression and for monoamine oxidase inhibition. The usual dosage isfrom to 200 mgm./ kg., although lesser or greater quantities may beused.

The following examples are intended to illustrate the inventiondescribed herein without unduly restricting it.

EXAMPLE 1 Preparation of N'-cyclopropyl a-chloroacetamide 01101 mQ/X-EXAMPLE 2 Preparation of N'-benZyl-N'-cyclopropyl a-chloroacetamide Amixture of 29 gm. (0.2 mol) of N-benzyl-N-cyclopropylamine and 65 ml. ofwater was cooled in an ice bath with good stirring, a-chloroacetylchloride (34 gm., 0.3 mol), and 8 gm. (0.2 mol) of NaOH in an equalvolume of water were added simultaneously and dropwise to the cold aminesolution. When the addition was completed, stirring was continued foranother 30 minutes and the solution was extracted with ether. Theethereal solution was washed twice with 10% NaOH, then water, dried withMgSO an filtered. Removal of the ether in vacuo yielded a residue whichwas fractionally distilled. Yield gm., B.P. 128130/0.15 mm. Hg.

A323, 3.08 and 6.08

EXAMPLE 3 Preparation of N'-2-phenylcyclopropyl u-chloroacetarnide2-phenylcyclopropylarnine (1.23 mol) was added to ml. Water and cooledin an ice-water bath. To the stirred mixture was added dropwise andsimultaneously 113 gm. (1.23 mol) a-chloroacetyl chloride and an aqueoussolution containing 50 gm. of sodium hydroxide. The amide separated as awhite solid and was collected by filtration. The solid was taken up inmethylene chloride and dried with Na SO Removal of the solvent yieldedN'-2-phenylcyclopropyl a-chloroacetamide.

EXAMPLE 4 When, in the procedure of Example 1, the cyclopropylamine isreplaced by an equal molar amount of 2-methylcyclopropylamine,2-ethylcyclopropylamine, 2-isopropylcyclopropylamine,2-phenylcyclopropylamine, 2-benzylcyclopropylamine,2-4-chlorophenylcyclophopylamine,2-4-trifiuoromethylphenylcyclopropylamine,2-4-methylphenylcyclopropylamine, 2-2-fluorophenylcyclopropylamine,2-3-methylphenylcyclopropylamine,

2-3 -brornophenylcyclopropylamine, 2-2,6-dich1orophenylcyclopropylamine,2-4-methylthiophenylcyclopropylamine,2-2-dimethylsulfamylphenylcyclopropylamine,2-2-iodo-4-methylphenylcyclopropylamine,2-4-isopropylphenylcyclopropylamine, 2-4-phenylphenylcyclopropylamine,2-3-phenoxyphenylcyclopropylamine, 2-4-benzylphenylcyclopropylamine,2-3,4-methylenedioxyphenylcyclopropylamine,2-4-fluorophenylcyclopropylamine,2-4-chlorobenzylphenylcyclopropylamine, 2-phenethylcyclopropylamine,2-allylcyclopropylamine, 2-propargylcyclopropylamine,2-1-butinylcyclopropylamine, 2-ethinylcyclopropylamine,2-ethenylcyclopropylamine, 2-1-propenylcyclopropylamine,2-3-butenylcyclopropylamine, 2-1-hexenylcyclopropylamine,2-phenylisopropylcyclopropylamine, 2-4-phenoxyphenylcyclopropylamine,2-cinnamylcyclopropylamine, 2-2,4-dimethylphenylcyclopropylamine, and2-4-trifiuoromethylcinnamylcyclopropylamine,

there are obtained,

N'-2-methylcyclopropyl a-chloroacetamide, N'-2-ethylcyclopropyla-chloroacetamide, N-2-isopropylcyclopropyl a-chloroacetamide,N'-2-phenylcyclopropyl a-chloroacetamide, N'-2-benzylcyclopropyla-chloroacetamide, N'-2-4-chlorophenylcyclopropyl a-chloroacetamide,N'-2-4-trifluoromethylphenylcyclopropyl a-chloroacetamide,N-2-4-methylphenylcyclopropyl a-chloroacetamide,N-2-2-fiuorophenylcyclopropyl ot-chloroacetamide,N-2-3-methylphenylcyclopropyl a-chloroacetamide,N'-2-3-bromophenylcyclopropyl a-chloroacetamide,N'-2-2,6-dichlorophenylcyclopropyl ot-chloroacetamide,N-2-4-methylthiophenylcyclopropyl u-chloroacetamide,N-2-Z-dimethylsulfamylphenylcyclopropyl a-chloroacetamide,N'-2-2-iodo-4-methylphenylcyclopropyl a-chloroacetamide,N-2-4-isopropylphenylcyclopropyl a-choloracetamide,N'-2-4phenylphenylcyclopropyl a-chloroacetamide,N'-2-3-phenoxyphenylcyclopropyl a-chloroacetamide,N'-2-4-benzylphenylcyclopropyl a-chloroacetamide,N-2-3,4-methylenedioxyphenylcyclopropyl a-chloroacetamide,N-2-4-fluorophenylcyclopropyl a-chloroacetamide,

N-2-4-chlorobenzylphenylcyclopropyl u-chloroacetamide,N-2-phenethylcyclopropyl a-chloroacetamide, N'-2-a1lylcyclopropyla-chloroacetamide, N-2-propargylcyclopropyl a-chloroacetamide,N'-2-l-butinylcyclopropyl u-chloroacetamide, N-2-ethinylcyclopropylu-chloroacetamide, N-2-ethenylcyclopropyl a-chloroacetamide,N'-2-l-propenylcyclopropyl a-chloroacetamide, N-2-3-buteuylcyclopropyla-chloroacetamide, N'-2-l-hexenylcyclopropyl a-chloroacetamide,N'-2-phenylisopropylcyclopropyl a-chloroacetamide,N-2-4-phenoxyphenylcyclopropyl a-chloroacetamide,N'-2-cinnamylcyclopropyl a-chloroacetamide,N-2-2,4-dimethylphenylcyclopropyl ot-chloroacetamide,

and N-2-4-trifluoromethylcinnamylcyclopropyl a-chloroacetamide,

respectively.

EXAMPLE When, in the procedure of Example 2, N-benzyl-N'-cyclopropylamine, is replaced by an equal molar amount ofN'-rnethyl-N'-cyclop ropylamine, N-isopropyl-N-cyclopropylamine,N-allyl-N'-cyclopropylamine, N'-propargyl-N-cyclopropylamine,N-phenethy1-N'-cyclopropylamine, N'-butyl-N-cyclopropyl amine,N'-ethinyl-N'-cyclopropylamine, N-cinnamyl-N-cyclopropylamine,N'-1-butinyl-N'-cyclopropylamine, N- l-propenyl-N'-cyclopropylamine,N'-methyl-N'-2-phenylcyclopropylamine, N-methyl-N'-2- (3-trifiuoromethyl phenylcyclopropylamine, N-allyl-N-2- (4-fluorophenylcyclopropylamine, N-propargyl-N-2- 3 ,4-methylenedioxy)phenylcyclopropylamine, N-benzyl-N'-2- (Z-methylthio)phenylcyclopropylamine, N-rnethy1-N-2-b enzylcyclopropylamine,N-methyl-N-2- (4-trifluoromethyl) phenylcyclopropylamine, N'-benzyl-N'-2-benzylcyclopropylamine,N-methyl-N'-2-2,6-dichlorophenylcyclopropylamine, andN-methyl-N'-2-2-methyl-4-trifluoromethylphenylcyclo propylamine,

there are obtained,

1 4 N'-methyl-N'-2-2-methyl-4-trifiuoromethylphenylcyclopropyla-chloroacetamide respectively.

EXAMPLE 6 Preparation of a-(N-benzyl-N-methyl)-amino-N'-cyclopropylacetamide To a gently refluxing solution ofa-chloro-N'-cyclopropylacetamide (131 gm., 0.97 mol) and triethylaminegm.) in benzene (2 liters) was added dropwise N-methylbenzenylamine gm.,1.0 mol). The solution was refluxed overnight, and upon cooling, thesalts were removed by filtration. Benzene was removed in vacuo to leavea residue of 226 gm. of crude a-(N-benZyl-N methyl)amino-N'-cyclopropylacetamide.

A portion of the crude product was purified by distillation, B.P. C./0.2 mm. On standing, the a-(N benzyl- N-methyl)amino-N'-cyclopropylacetamide crystallized, and after Washing withpetroleum ether, showed a melting point of 49-52 C., and infraredabsorption spectra as follows:

max.

3.06, 6.02, 6.55, 13.50 and 14.40;].

#:333 307, 6.03, 0.50, 13.50 and 14.40,.

EXAMPLE 7 Preparation of N-benzyl-N-methyl-N'-cyclopropylethylenediaminen Q-om-If-ornom-rr-Q oc-(N'b6nZY1 N methyl)amino N cyclopropylacetamide,prepared in Example 6, was dissolved in tetrahydrofuran (anhydrous) andadded dropwise to a suspension of lithium aluminum hydride (43 gm.) inwhy drous tetrahydrofuran (1 liter). After completion of the addition,the mixture was refluxed with stirring for 3 hours to complete thereduction. The mixture was cooled in an ice bath and the excess lithiumaluminum hydride was destroyed by the addition of a saturated aqueoussodium sulfate solution. Upon removal of the tetrahydrofuran in vacuo,an oil remained which was dissolved in ether, dried over anhydrouspotassium carbonate and purified by fractional distillation, B.P. 7072C./0.10- 0.15 mm., to yield 167 gm. of N-benzyl-N-methyl-N'-cyclopropylethylenediamine.

EXAMPLE 8 Preparation of N-benZyl-N-methyl-N'-cyclopropylethylenediaminedihydrochloride N-benzyl N methyl-N-cyclopropylethylenediamine, preparedin Example 7, was dissolved in ethanol, and converted to itsdihydrochloride by the addition of an excess of ethanolic HCl.

157 gm. of N-benZyl-N-methyl-N'-cyclopropylethylenediaminedihydrochloride were obtained having a melting point of 230231 C., andthe following analysis:

Calcd for C H CI N (percent): C, 56.36; H, 8.01; N, 10.11; Cl, 25.60.Found (percent): C, 56.44; H, 8.73; N, 9.80; CI, 25.46.

EXAMPLE 9 Preparation of N-benzyl-N-methyl-N'-cyclopropyl-N'-formylethylenediamine r- -Kl CH3 HC=O To a chloroform solutioncontaining N-benZyl-N-methyl-N-cyclopropylethylenediamine (8.0 gm.,0.022 mol) prepared in Example 7, was added chloral (5.3 gm.).

max.

6.00, 13.60 and 14.40u

EXAMPLE 10 Preparation of N-benzyl-N'-cyclopropyl-N,N'-dimethylethylenediamine @W w-Q N-benzyl Nmethyl-N'-cyclopropyl-N'-formylethylenediamine, prepared in Example 9,was dissolved in tetrahydrofuran (anhydrous) and added dropwise to asuspension of lithium aluminum hydride (3.5 gm.) in anhydroustetrahydrofuran (1 liter). After completion of the addition, the mixturewas refluxed with stirring for 3 hours to complete the reduction. Themixture was colled in an ice bath and the excess lithium aluminumhydride was destroyed by the addition of a saturated aqueous sodiumsulfate solution. Upon removal of the tetrahydrofuran in vacuo, 5.2 gm.of the product, N- benzyl N cyclopropyl-N,N'-dimethylethylenediamine,was collected by distillation, B.P. 95100 C./0.2 mm., having an infraredabsorption spectrum as follows:

A231, no band at 6.00, band at 13.65 and 14.40;; This indicates completereduction of the formyl group.

EXAMPLE 11 Preparation ofN-benzyl-N'-cyclopropyl-N,N-dimethylethylenediamine dihydrochlorideN-benzyl N cyclopropyl-N,N'-dimethylethylenediamine, prepared in Example10, was converted to the dihydrochloride salt with gaseous HCl inethanol, yielding 4.8 gm. of N-benzyl-N'-cyclopropyl N,Ndimethylethylenediamine dihydrochloride, which had a melting point of117-119 C.

EXAMPLE 12 Preparation of N-bnezyl-N-methyl-N'-cyclopropyl-N-propargylethylenediamine CHzCECH To a refluxing solution (undernitrogen) of N-benzyl- N-methy1-N'-cyclopropyl-1,2-diaminoethane (12.7gm., 0.062 mol) in tetrahydrofuran (100 ml.) was added dropwise 32.6 ml.of 2 N CH MgBr solution. After evolution of methane ceased, 7.4 gm.(0.062 mol) of propargyl bromide in benzene (150 ml.) was added to thereaction mixture and refluxed for 3 hours. The solution was treated withwater (100 ml.), the benzene layer was decanted, and the aqueous partwas extracted twice With benzene. After drying, the benzene was removedand the residue distilled. Material with a B.P. of 95100 C./ 0.15 mm.,was collected, yielding 5.2 gm. of N benzyl-N- methyl Ncyclopropyl-N-propargylethylenediamine which had an infrared spectrum asfollows:

AL'S. 3.05, 13.75 and 14.40,.

EXAMPLE 13 Preparation of N-benzyl-N-methyl-N-cyclopropyl-N'-propargylethylenediamine dihydrochloride N benzyl Nmethyl-N-cyclopropyl-N'-propargylethylenediamine, prepared in Example12, was converted to the dihydrochloride salt with gaseous HCl inethanol. Removal of ethanol yielded a gum which crystallized from alittle ethanol after standing overnight at room temperature, and whichhad a melting point of 164.4- 169.5 C. Recrystalization fromethanol-ether yielded 4.8 gm. of N benzyl Nmethyl-N-cyclopropyl-N'-propargylethylenediamine dihydrochloride, havinga melting point of 165166 C., and an infrared absorption spectrum asfollows:

M3,"; 3.05, 13.45, 14.35, 14.80 and 15.70;;

EXAMPLE 14 Preparation of a-(N-benzyl-N-methyl)amino-N'-2-phenylcyclopropylacetamide To a gently refluxing solution of 21.2 gm.(0.10 mol) of 0c chloro-N'-2-phenylcyclopropylacetamide and 11.0 gm.triethylamine in 250 cc. of benzene was added dropwise 14.3 gm. (0.11mol) of N-benzyl-N-methylamine and the solution refluxed for 20 hours.After removal of the salts and the benzene, the product, a-(N-benzyl-Nmethyl)amino-N 2 phenylcyclopropylacetamide, was subjected to reductionwithout further purification as shown in the subsequent example.

EXAMPLE 15 Preparation ofN-benzyl-N-methylN-2-phenylcyclopropylethylenediamine H CHH HMHPNQa(Nbenzyl N methyl)a1nino-N'-2 phenylcyclopropylacetamide, prepared inExample 14, was dissolved in tetrahydrofuran (anhydrous) and addeddropwise to a suspension of lithium aluminum hydride (43 gm.) andanhydrous tetrahydrofuran (1 liter). After completion of the addition,the mixture was refluxed with stirring for 3 hours to complete thereduction. The mixture was cooled in an ice bath and the excess lithiumaluminum hydride was destroyed by the addition of a saturated aqueoussodium sulfate solution. Upon removal of the tetrahydrofuran in vacuo,an oil remained which was dissolved in ether, dried over anhydrouspotassium carbonate and purified by fractional distillation, B.P. 118C./0.10 mm., to yield 15 gm, ofN-benzyl-N-methyl-N'-2-phenylcyclopropylethylenediamine.

EXAMPLE 16 Preparation of u-(N-m-trifiuoromethylbenzyl-N-methyl)-amino-N-cyclopropylacetamide CH3 OFs a-Chloro-N-cyclopropylacetamide isreacted with N- m-trifluoromethylbenzyl-N=methylamine (obtained from thereaction of m-chloromethylbenzotrifiuoride and excess methylamine) inthe manner described in Example 6, to producea-(N-m-trifluoromethylbenzyl N methyl)- amino-N'-cyclopropylacetamide.

EXAMPLE 17 Preparation of N-m-trifluoromethylbenzyl-N-methyl-N'-cyclopropylethylenediamine CHa OFa a-(N-m-trifluoromethylbenzyl Nmethyl)amino N'- cyclopropylacetamide, prepared in Example 16, isreduced respectively.

EXAMPLE 26 When, in the procedure of Example 6, -a-chloro-N-cyclopropylacetamide is replaced by an equal molar amount ofa-chloro-N-benzyl-N'-cyclopropylacetamide and N-methylbenzylamine isreplaced by an equal molar amount of N-methyl-N-propargylamine,N-ethinyl-N-propargylamine, N-isopropyl-N-propargylamine,N-allyl-N-propargylamine, N-butenyl-N-propargylamine,N-propargyl-N-propargylamine, N-cyclopropyl-N-propargylamine,N-methyl-N-ethinylamine, and N-methyl-N-butinylamine,

there are obtained,

a-N-methyl-N-propargylamino-N'-benzyl-N'- cyclopropylacetamide,a-N-ethinyl-N-propargylamino-N'-benzyl-N'- cyclopropylacetamide,a-N-isopropyl-N-propargylamino-N-benzyl-N'- cyclopropylacetamide,a-N-allyl-N-propargylamino-N'-benzyl-N'- cyclopropylacetamide,a-N-butenyl-N-propargylamino-N-benzyl-N'- cyclopropylacetamide, a-N-propargyl-N-propargylamino-N'-benzyl-N'- cyclopropylacetamide,a-N-cyclopropyl-N-propargylamino-N-benzyl-N'- cyclopropylacetamide,a-N-methyl-N-ethinylamino-N'-benzyl-N- I cyclopropylacetarnide, anda-N-methyl-N-butinylamino-N-benzyl-N- cyclopropylacetamide,

respectively.

EXAMPLE 27 When, in the procedure of Example 7, a-(N-benzyl-N-methyl)amino-N'-cyclopropylacetamide is replaced by an equal molaramount of each of the products of Example 26, there are obtained,

N-methyl-N-propargyl-N'-benzyl-N-cyclopropylethylenediamine,N-ethinyl-N-propargyl-N'-benzyl-N'-cyclopropylethylenediamine,N-isopropyl-N-propargyl-N-benzyl-N'-cyclopropylethylenediamine,N-allyl-N-propargyl-N'-benzyl-N'-cyclopropylethylenediamine,N-butenyl-N-propargyl-N'-benzy1-N'-cyclopropylethylenediamine,N-propargyl-N-propargyl-N'-benzyl-N-cyclopropylethylenediamine,

26 N-cyclopropyl-N-propargyl-N-benzyl-N-cyclopropylethylenediamine, N-methyl-N-ethinyl-N'-benzyl-N-cyclopropylethylenediamine, andN-methyl-N-butinyl-N'-benZy1-N'-cyclopropylethylenediamine,

respectively.

EXAMPLE 28 Preparation of a-(N-cyclopropyl-N-benzyl)aminoN'-methylacetamide CH3 CH2 A benzene solution ofa-chloro-N-methylacetamide (18.3 gm., 0.17 mol) was added dropwise to arefluxing mixture of N-cyclopropyl-N-benzylamine (25 gm., 0.17 mol) and17.2 gm. of triethylamine in benzene and the reaction was allowed toproceed overnight. The solution was cooled, triethylamine-HCI wasremoved by filtration and the solution was concentrated in vacuo toyield 36.7 gm. of a residue. A portion of the crude amide, 3.0 gm, wasdistilled to give a-(N-cyclopropyl-N-benzyl)amino- N-methylacetamide,B.P. 147l53/ 0.07 mm. Hg. Yield 2.4 gm.

CHCI A a 2.95, 6.03, 6.52,.

EXAMPLE 29 N-methyl-N'-benzyl-N-cyclopropylethylenediamine CH3 CH3 a-(Ncycloipropyl N benzyl)amino-N'-methylacetamide, 33.7 gm., was reducedwith 10 gm. lithium aluminum hydride in tetrahydrofuran by refluxingovernight. Excess lithium aluminum hydride was destroyed with saturatedNa SO solution and the tetrahydrofuran was removed by distillation atatmospheric pressure. The residue was distilled to yield a liquid,N-methyl-N-benzyl- N-cyclopropylethylenediamine, B.P. 127129.5/mm.;yield, 32.2 gm.

A dihydrochloride was prepared with 6.0 gm. of the diamine fromethanolic HCl. Removal of solvent gave a gum which was crystallized fromethanol-ether. The solid was recrystallized from ethanol-ether and driedin a desiccator. Yield, 5.5 gm. ofN-methyl-N-benzyl-N'-cyclopropylethylenediamine dihydrochlorid'e, M.P.148 C.

Analysis.Calcd for C H N Cl (percent): C, 56.36; H, 8.01; N, 10.11; Cl,25.60. Found (percent): C, 56.16; H, 8.04; N, 10.26; Cl, 25.80.

EXAMPLE 30 Preparation of N-methyl-N-propargyl-N'-benzyl-N-cyclopropylethylenediamine To a refluxing solution ofN-rnethyl-N-benzyl-N'-cyclopropylethylenediamine, 13.8 gm. (0.06 mol) intetrahydrof uran was added 33 ml. of 2 N CH MgBr. When evolution of gasceased, 7.2 gm. of propargyl bromide in 100 ml. of dry benzene was addeddropwise. After 3 hours refluxing, the solution was cooled, 100 ml.water was added, and the benzene layer was decanted. The Water layer wasagain extracted twice more with benzene and the benzene extracts weredried and made free of solvent. An oil, 16.7 gm. was obtained which wasdistilled to yield 8.0 gm. of N-methyl-N-propargyl-N-benzyl-N'-cyclopropylethylenediamine; B.P. 99-1 14/ 0.09 mm.

A crystalline dihydrochloride was obtained from ethanolether andrecrystallized from the same solvent system to yield 5.4 gm. ofN-methyl-N-propargyl-N'-benzyl-N'- cyclopropylethylenediaminedihydrochloride; M.P. 171- 174 C. with decomposition.

Thus, it is apparent from the foregoing description that the objects ofthis invention have been attained. Novel compounds have been inventedwhich have antidepressant activity and inhibit monoamine oxidase. Inaddition, a novel method of treating depression has been invented.

While this invention has been described and exemplified in terms of itspreferred embodiment, those skilled in the art will appreciate thatmodifications can be made without departing from the spirit and scope ofthis invention.

We claim:

1. A compound of the formula R is a member selected from the groupconsisting of hydrogen (lwer)alkyl, (lower)alkenyl, (lower)alkynyl,phenylalkyl, wherein the alkyl moiety contains from 1 to 4 carbon atoms,inclusive, and phenylalkenyl, wherein the alkenyl moiety contains from 2to 4 carbon atoms, inclusive; and

R is a member selected from the group consisting of hydrogen,(lower)alkyl, (1ower)alkenyl, (lower) alkynyl, Ph-, Ph-alk-, andPh-alken-, wherein alk represents a divalent alkylene radical containingfrom 1 to 4 carbon atoms, inclusive, alken represents a divalentalkenylene radical containing from 2 to 4 carbon atoms, inclusive, andPh represents a radical of the formula wherein R and R are each a memberselected from the group consisting of hydrogen, chloro, bromo, iodo,fiuoro, trifluoromethyl, (lower)alkyl, (lower)alkoxy, (lower) alkylthio,phenyl, phenoxy, and benzyl;

and the pharmaceutically acceptable nontoxic salts there- 2. Thecompound of claim 1 having the formula 3. A pharmaceutically acceptablenontoxic salt of the compound of claim 2.

4. The compound of claim 1 having the formula 5. The compound of claim 1having the formula 6. The compound of claim 1 having the formula 7. Thecompound of claim 1 having the formula 8. A compound of claim 1 havingthe formula 9. A compound of claim 1 having the name N-butenyl-N-propargyl-N'-benzyl-N-cyclopropylethylenediamine.

10. A compound of claim 1 having the formula References Cited UNITEDSTATES PATENTS 3,365,458 1/1968 Biel et al. 260570.5 X

ROBERT V. HINES, Primary Examiner UNITED STATES PATENT OFFICE (l F F FCERTIFICATE OF CORRECTION Pat-ant No, I 3 53 ,7 9 7 Dated OCtober 6,1970 e, John H. Biel and Edward J. War'awa It is certified that errorappears in vthe above-identified patent and that said Letters Patent arehetgby cot-rented as shown ba'law:

In the Claims, Claim 10 should read:

SIGNED AND Q EALED (SEAL) Edwardmliletchmlr. C

wmmuux. mm. m.

L Oflioer Gamissiom of Patents:

